Metabolic, epigenetic and transcriptomic alterations in postnatal 16p11.2 deficient murine astrocytes

Abstract

Autism Spectrum Disorders (ASD) are associated with metabolic dysregulation. While astrocytes are integral to cerebral metabolism, their molecular and functional changes in ASD are poorly known. Using early postnatal primary cortical astrocytes from a mouse model of 16p11.2 deletion ASD syndrome (16p11.2df/+ mice), we observed core molecular alterations with sex-specific profiles, suggesting divergent energetic pathways and epigenetic regulation. Targeted metabolomics revealed opposing phenotypes in male versus female 16p11.2df/+ astrocytes, particularly for alpha-ketoglutaric acid. Functionally, 16p11.2df/+astrocytes exhibited elevated phosphorylation in low glucose culture conditions, and reduced glycolysis in high glucose. Epigenetic profiling of male 16p11.2df/+astrocytes revealed differentially hydroxymethylated and methylated regions, with foci on chromosomes 3 and 13. Finally, bulk RNA sequencing in male and female mutant astrocytes indicated differential gene expression with profound sex differences, mostly affecting pathways related to cellular morphology. By establishing 16p11.2df/+ astroglial molecular signatures, this study refines our understanding of glial changes in ASD.